Derivatives of 1-(oxoaminoacetyl) pentylcarbamate as cathepsin K inhibitors for the treatment of bone loss
AssigneeSmithKline Beecham Corporation
InventorsDavid Gene Barrett, John G. Catalano, David Norman Deaton, Aaron Bayne Miller, John A. Ray, Vicente Samano
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Abstract
Heterocycle substituted ketoamide derivatives of Formula (I), wherein the substitutes A, D, A and R are defined as in claim in, which are useful as cathepsin K inhibitors are described herein. The described invention also includes methods of making such heterocycle substituted ketoamide derivatives as well as method of using the same in the manufacture of medicaments for the treatment of disorders, including osteoporosis, associated with an imbalance between bone resorption and formation which can ultimately lead to fracture.
Claims46
A compound of Formula (I):
- or a salt or solvate thereof wherein
- A is the group defined by (Q4)p-(Q3)n-(Q2)m-(Q1)-, wherein
- Q1 is heterocyclyl or heterocyclylene,
- Q2 is OC(O), C(O), N(H)C(O), C(O)N(H)C(O), S(O)2N(H)C(O), S(O)2, or N(H)S(O)2 and m is 0 or 1,
- Q3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, aralkyl, aralkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene, and n is 0 or 1, and
- Q4 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, aryloxy, heteroaryl, halo, or cyano, and p is 0, 1, or 2;
- D is O or S;
- R is hydrogen or —N(R1)—R2—R3;
- R1 is hydrogen or C1-C6 alkyl;
- R2 is C(O), C(O)O, C(O)N(H), SO2, or SO2N(H);
- R3 is hydrogen or C1-C6 alkyl;
- Z is the group defined by —(X)t—(X1), wherein
- X is C(R′)(R″), wherein R′ is hydrogen or C1-C6 alkyl, R″ is hydrogen or C1-C6 alkyl, and t is 0, 1, or 2;
- and
- X1 is aryl, heteroaryl, or heterocyclyl.
A compound of Formula (II):
- or a salt or solvate thereof wherein
- A′ is the group defined by (Q4)p-(Q3)n-(Q2)m, wherein
- Q2 is OC(O), C(O), N(H)C(O), C(O)N(H)C(O), S(O)2N(H)C(O), S(O)2, or N(H)S(O)2 and m is 0 or 1,
- Q3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, aralkyl, aralkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene, and n is 0 or 1, and
- Q4 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, aryloxy, heteroaryl, halo, or cyano, and p is 0, 1, or 2;
- Ra is hydrogen or oxo;
- Rb is hydrogen or C1-C6 alkyl;
- Rc is hydrogen or C1-C6 alkyl;
- R is hydrogen or —N(R1)—R2—R3;
- R1 is hydrogen or C1-C6 alkyl;
- R2 is C(O), C(O)O, C(O)N(H), SO2, or SO2N(H);
- R3 is hydrogen or C1-C6 alkyl;
- Z is the group defined by —(X)t—(X1), wherein
- X is C(R′)(R″), wherein R′ is hydrogen or C1-C6 alkyl, R″ is hydrogen or C1-C6 alkyl, and t is 0, 1, or 2;
- and
- X1 is aryl, heteroaryl, or heterocyclyl.
Dependencies are inferred from the claim text.